Control of arthropods in animals

ABSTRACT

A method of controlling parasites in or on an animal comprising orally administering to the animal a parasiticidally effective, substantially non-emetic 1-arylpyrazole.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 09/457,869, filed Dec. 10, 1999, now U.S. Pat. No. 6,160,002, incorporated by reference herein in its entirety and relied upon, which claims the priority of U.S. Provisional Application No. 60/111,857, filed Dec. 11, 1998, and of U.S. Provisional Application No. 60/140,680, filed Jun. 24, 1999, both incorporated by reference in their entireties and relied upon.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method of control of parasites in animals, compositions comprising a compound effective for said control and new compounds effective against parasites.

2. Related Art

The state of the art is represented by Hatton et al U.S. Pat. No. 5,232,940, Stetter et al U.S. Pat. No. 5,580,843, Huang et al U.S. Pat. No. 5,556,873, EP 0511845, WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278, WO 98/28279, EP 0295117, EP 0846686, EP 0659745, WO 97/22593 and EP 0811615.

It is generally a goal of agronomists and veterinarians to possess sufficient means to control pests, particularly arthropods, when they attempt to invade or attack mammals, particularly domestic animals and/or livestock. A classical method of controlling such pests has been the use of topical and/or systemic pesticides on or in the domestic animal which is being attacked. Generally effective treatments include the oral administration of insect growth regulators, such as lufenuron, or antihelminth compounds such as an ivermectin or an avermectin, or the topical application of the insecticide fipronil. It is advantageous to apply pesticides to animals in oral form so as to prevent the possible contamination of humans or the surrounding environment.

SUMMARY AND OBJECTS OF THE INVENTION

It is an object of the present invention to provide new pesticides which may be used in domestic animals.

Another object of the invention is to provide safer pesticides for domestic animals.

Another object of the invention is to provide new pesticides for domestic animals that are may be used in lower doses than existing pesticides.

These objects are met in whole or in part by the present invention.

The present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (I):

wherein:

R₁ is cyano, acetyl, C(S)NH₂, alkyl, haloalkyl, C(═NOH)NH₂ or C(═NNH₂)NH₂;

R₂ is S(O)_(n)R₃, C₂-C₃ alkenyl, C₂-C₃ haloalkenyl, cycloalkyl, halocycloalkyl or C₂-C₃ alkynyl;

R₃ is alkyl or haloalkyl;

R₄ is —N═C(R₅)—Z—R₆, —N═C(R₅)—N(R₇)—R₈, or —N(R₉)—C(R₅)═NR₆;

R₅ is hydrogen, alkyl, or alkyl substituted by halogen, alkoxy, haloalkoxy or —S(O)_(m)R₁₅;

R₆ and R₇ each independently represent hydrogen, alkyl, C₃-C₅ alkenyl or C₃-C₅ alkynyl; or

alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; or

R₆ and R₇ may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;

R₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, R₁₄CO— or —S(O)_(t)R₁₀;

R₉, R₁₀ and R₁₄ are alkyl or haloalkyl;

R₁₁ and R₁₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(q)CF₃, and —SF₅;

R₁₅ is alkyl or haloalkyl;

X is selected from nitrogen and C—R₁₂;

Z is O, S(O)_(a), or NR₇;

a, m, n and q are independently selected from 0, 1, and 2; and

t is 0 or 2;

and veterinarily acceptable salts thereof.

In another aspect, the present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (XX):

wherein:

R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(═NOH)NH₂ or C(═NNH₂)NH₂;

R₂₀₂ is S(O)_(h)R₂₀₃, C₂-C₃ alkenyl, C₂-C₃ haloalkenyl, cycloalkyl, halocycloalkyl or C₂-C₃ alkynyl;

R₂₀₃ is alkyl or haloalkyl;

R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈, —N(R₂₀₅)C(O)aryl, or —N(R₂₀₅)C(O)OR₂₀₇;

R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl, alkoxyalkyl, haloalkoxyalkyl, C₃-C₅ alkenyl, C₃-C₅ haloalkenyl, C₃-C₅ alkynyl, C₃-C₅ haloalkynyl;

R₂₀₆ is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkyl amino, dialkylamino, haloalkylamino, di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy, alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy, or arylalkoxy;

R₂₀₇ and R₂₀₈ are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; or R₂₀₇ and R₂₀₈ may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

X₁ is selected from nitrogen and C—R₂₁₂;

R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃, and —SF₅; and

h and k are independently selected from 0, 1, and 2;

and veterinarily acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

By the term “veterinarily acceptable salts” is meant salts the anions of which are known and accepted in the art for the formation of salts for veterinary use. Suitable acid addition salts, e.g. formed by compounds of formulae (I) and (XX) containing a basic nitrogen atom, e.g. an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids for example acetic acid.

Unless otherwise specified, alkyl and alkoxy groups here and throughout this specification are generally lower alkyl and alkoxy groups, that is having from one to six carbon atoms, preferably from one to four carbon atoms. Generally, the haloalkyl, haloalkoxy and alkylamino groups have from one to four carbon atoms. The haloalkyl and haloalkoxy groups can bear one or more halogen atoms; preferred groups of this type include —CF₃ and —OCF₃. Cycloalkyl groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms and may be substituted by one or more halogen atoms. Alkenyl, haloalkenyl, alkynyl, and haloalkynyl groups generally contain from 3 to 5 carbon atoms. By the term aryl is generally meant phenyl, pyridyl, furyl, and thiopheneyl (thienyl), each of which is optionally substituted by one or more halogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, hydroxy, amino, alkylamino or dialkylamino. In compounds of formula (I), by the term substituted alkyl is meant alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two. Preferably in compounds of formula (I), alkyl groups are generally substituted by from one to five halogen atoms, preferably from one to three halogen atoms. Chlorine and fluorine atoms are preferred.

The above definitions of alkyl, alkoxy and various-other groups of course pertain not only to those radicals themselves but also to those portions of larger radicals.

Compounds of formula (I) wherein R₄ is —N═C(R₅)—Z—R₆, Z is NR₇ and R₆ represents a hydrogen atom may exist as the tautomeric double bond isomer form —NH—C(R₅)═N—R₇. It is to be understood that both such forms are embraced by the present invention.

In compounds of formula (XX) the following examples of radicals are provided:

An example of cycloalkylalkyl is cyclopropylmethyl;

an example of cycloalkoxy is cyclopropyloxy;

an example of alkoxyalkyl is CH₃OCH₂—;

an example of alkoxyalkoxy is CH₃OCH₂O—;

An example of alkoxyalkoxyalkoxy is CH₃OCH₂OCH₂O—;

An example of aryloxy is the phenoxy radical; and

An example of the arylalkoxy radical is benzyloxy or 2-phenylethoxy.

Generally, in dialkylamino or di(haloalkyl)amino radicals, the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another.

It is also to be understood that enantiomeric and diastereomeric forms of the compounds of formulae (I) and (XX) and salts thereof are embraced by the present invention. Compounds of formula (I) may be generally prepared according to known processes, for example as described in European Patent Publication 0511845 or other processes according to the knowledge of a man skilled in the art of chemical synthesis.

By the term “non-emetic” is meant a compound or composition that does not generally elicit emesis from the animal when a protective, preventative or cleaning dose is administered to the animal. By the term “emesis” is meant vomiting. Generally an emetic substance elicits emesis in less than 24 hours after administration, usually less than 8 hours, more usually less than 2 hours. By the term “substantially non-emetic” is meant that, generally, when a compound or composition of the invention is administered to a population of animals, more than 70% (or at least ⅔) of the animals are free of emesis. Preferably, more than 80%, most preferably more than 90%, of said population is free of emesis.

A preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano or alkyl;

R₂ is S(O)_(n)R₃;

R₃ is alkyl or haloalkyl;

R₄ is —N═C(R₅)—Z—R₆;

R₅ is hydrogen, alkyl or haloalkyl;

Z is O, S(O)_(a), or NR₇;

R₆ and R₇ are independently selected from hydrogen and unsubstituted or substituted alkyl; or

R₆ and R₇ may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;

X is selected from nitrogen and C—R₁₂;

R₁₁ and R₁₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(q)CF₃ and —SF₅;

a, n and q are independently selected from 0, 1, and 2.

Preferably R₆ is alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, sulfide, sulfoxide, sulfone, or phenyl or pyridyl moieties of which each phenyl or pyridyl moiety is optionally substituted with one or more groups selected from halo, nitro, and alkyl.

Preferably the method of the invention has one or more of the following features:

R₁ is cyano;

R₄ is —N═C(R₅)—Z—R₆ and Z is —NR₇;

X is C—R₁₂; R₁₁ and R₁₂ represent a chlorine atom; and R₁₃ is CF₃, OCF₃ or —SF₅;

R₁₂ is —S(O)_(n)CF₃ and n is 0, 1, or 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano or alkyl; R₄ is —N═C(R₅)—Z—R₆; and R₅ is hydrogen or C₁-C₃ alkyl.

The compounds of formula (I) for use in the control of parasites in animals preferably have one or more of the following features:

R₁ is cyano or methyl;

R₃ is halomethyl (preferably CF₃);

R₁₁ and R₁₂ each independently represent a halogen atom;

X is C—R₁₂;

R₁₃ is haloalkyl (preferably CF₃), haloalkoxy (preferably OCF₃), or —SF₅; or

n is 0, 1 or 2 (preferably 0 or 1).

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n)R₃;

R₃ is halomethyl;

R₄ is —N═C(R₅)—Z—R₆;

Z is NR₇;

R₅ is hydrogen or alkyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

X is selected from nitrogen and C—R₁₂;

R₁₁ and R₁₂ each independently represent a halogen atom;

R₁₃ is selected from haloalkyl, haloalkoxy and —SF₅;

R₁₅ is alkyl or haloalkyl; and

m and n are independently selected from 0, 1, and 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals is that wherein:

R₁ is cyano;

R₂ is S(O)_(n)CF₃;

R₄ is —N═C(R₅)—Z—R₆ or —N═C(R₅)—N(R₇)—R₈;

Z is NR₇;

R₅is hydrogen or alkyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

R₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or —S(O)_(t)R₁₀;

X is selected from nitrogen and C—R₁₂;

R₁₀ and R₁₅ independently represent alkyl or haloalkyl;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or —SF₅; and

m and n are 0, 1 or 2; and t is 0 or 2.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n)CF₃;

R₄ is —N═C(R₅)—Z—R₆;

Z is NR₇;

R₅ is hydrogen or methyl;

R₆ and R₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;

X is C—R₁₂;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or —SF₅;

R₁₅ is alkyl or haloalkyl;

m is zero, one or two; and

n is 0or 1.

A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:

R₁ is cyano;

R₂ is S(O)_(n)CF₃;

R₄ is —N═C(R₅)—Z—R₆;

Z is NR₇;

R₅ and R₇ each represent a hydrogen atom;

R₆ is alkyl or haloalkyl;

X is C—R₁₂;

R₁₁ and R₁₂ each represent a chlorine atom;

R₁₃ is CF₃ or —SF₅; and

n is 0.

Compounds of formula (XX) which are preferred according to the present invention are those wherein:

R₂₀₁ is cyano;

R₂₀₂ is S(O)_(h)R₂₀₃;

R₂₀₃ is alkyl or haloalkyl;

R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈;

R₂₀₅ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and halocycloalkylalkyl;

R₂₀₆ is alkoxy, haloalkoxy, or hydrogen;

R₂₀₇ and R₂₀₈ are independently hydrogen, alkyl, or haloalkyl; or

R₂₀₇ and R₂₀₈ may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

X₁ is selected from nitrogen and C—R₂₁₂;

R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, S(O)_(k)CF₃, and —SF₅; and

h and k are independently selected from 0, 1, and 2.

A preferred group of compounds of formula (XX) is that wherein the ring which is formed by R₂₀₇ and R₂₀₈ is interrupted by one or more heteroatoms, more preferably one oxygen atom.

The compounds of formula (XX) of the present invention preferably have one or more of the following features:

R₂₀₁ is cyano;

R₂₀₃ is halomethyl, preferably CF₃;

R₂₁₁ and R₂₁₂ are independently halogen;

X₁ is C—R₂₁₂;

R₂₁₃ is haloalkyl, haloalkoxy or —SF₅; or

h is 0 or 1, or 2, preferably 0 or 1.

A preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈.

Another preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)aryl.

Another preferred class of compounds is that wherein R₂₀₄ is N(R₂₀₅)C(O)OR₂₀₇.

Preferably R₂₀₅ is C₁-C₄ alkyl, more preferably C₁-C₂ alkyl, most preferably methyl.

Preferably R₂₀₆ is alkoxy, most preferably methoxy, ethoxy or propoxy.

Preferably R₂₀₇ and R₂₀₈ are both hydrogen.

Among the compounds which may be used in the invention some are new and hence in another aspect of the present invention there is provided a compound of formula (II):

wherein:

R₂₁ is cyano, alkyl, haloalkyl, acetyl, —C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂;

R₂₂ is S(O)_(m)R₂₃;

R₂₃ is alkyl or haloalkyl;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇) or —N═C(R₂₅)—N(R₂₇)—R₂₈;

R₂₅ represents hydrogen or alkyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy or —S(O)_(m)R₃₅;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₃₅; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₃₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C—R₃₂;

R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or —S(O)_(t)R₃₀;

R₃₀ is alkyl or haloalkyl;

R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₃₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃, and —SF₅;

m and r are independently selected from 0, 1, and 2; and t is 0 or 2; with the exclusion of the compound wherein R₂₁ is cyano; R₂₂ is —SCF₂CH₃; R₂₅ is hydrogen; X is C—R₃₂; R₂₆ and R₂₇ are methyl; R₃₁ and R₃₂ are chlorine; and R₃₃ is trifluoromethyl; and veterinarily acceptable salts thereof.

A further class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano or methyl;

R₂₂ is S(O)_(m)R₂₃;

R₂₃ is haloalkyl;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ are hydrogen or unsubstituted or substituted alkyl;

R₂₆ is haloalkyl;

X is selected from nitrogen and C—R₃₂;

R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN and NO₂;

R₃₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(r)CF₃, and —SF₅;

m and r are independently selected from 0, 1, and 2; with the exclusion of the compound wherein R₂₁ is cyano; R₂₂ is —SCF₂CH₃; R₂₅ is hydrogen; X is C—R₃₂; R₂₆ and R₂₇ are methyl; R₃₁ and R₃₂ are chlorine; and R₃₃ is trifluoromethyl.

A preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m)R₂₃;

R₂₃ is halomethyl;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ is hydrogen or alkyl;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C—R₃₂;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is selected from haloalkyl, haloalkoxy and —SF₅;

m is selected from 0, 1, and 2.

A further preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m)CF₃;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇); or —N═C(R₂₅)—N(R₂₇)—R₂₈;

R₂₅ is hydrogen or methyl;

R₂₆ and R₂₇ each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

R₂₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or —S(O)_(t)R₃₀;

X is selected from nitrogen and C—R₃₂;

R₃₀ is alkyl or haloalkyl;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or —SF₅; and

m is 0, 1 or 2; and t is 0 or 2.

A more preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m)CF₃;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ each independently represent hydrogen or methyl;

R₂₆ represents hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₅; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₅ is alkyl or haloalkyl and m is zero, one or two;

X is selected from nitrogen and C—R₃₂;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or —SF₅; and

m is 0, 1 or 2.

An especially preferred class of novel compounds of formula (II) are those wherein:

R₂₁ is cyano;

R₂₂ is S(O)_(m)CF₃;

R₂₄ is —N═C(R₂₅)N(R₂₆)(R₂₇);

R₂₅ and R₂₇ each represent a hydrogen atom;

R₂₆ is alkyl or (preferably) haloalkyl;

X is C—R₃₂;

R₃₁ and R₃₂ each represent a chlorine atom;

R₃₃ is CF₃ or —SF₅; and

m is 0.

In another aspect of the present invention there is provided a compound of formula (XX) or a salt thereof as hereinbefore defined, provided that the compound is not 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(N-ethoxycarbonyl-N-methyl)amino-4-trifluoromethylthiopyrazole.

Most preferably, the following compounds of formulae (I) and (XX) are preferred according to the present invention as listed in Tables 1 to 13. The Compound Numbers are for identification purposes only. The following symbols are hereby defined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; n-Bu means n-Butyl, and n-Pent means n-Pentyl; Cy means cyclopropyl.

TABLE 1 Compounds of formula (I) wherein R₁ is cyano, R₂ is SCF₃, R₁₁ is Cl, X is C—Cl, R₄ is —N = C(R₅)ZR₆, Z is NR₇, R₇ is H, and R₁₃ is CF₃ or SF₅. Compound Compound Number Number R₁₃ = CF₃ R₁₃ = SF₅ R₅ R₆ 201-1 201-2 Me Me 202-1 202-2 Me Et 203-1 203-2 Me n-Pr 204-1 204-2 Me i-Pr 205-1 205-2 Me n-Bu 206-1 206-2 H H 207-1 207-2 H Et 208-1 208-2 H n-Pr 209-1 209-2 H i-Pr 210-1 210-2 H n-Bu 211-1 211-2 H CH₂CF₃ 212-1 212-2 H (CH₂)₂CF₃ 213-1 213-2 H CH₂OMe 214-1 214-2 H (CH₂)₂OCF₃ 215-1 215-2 Me CH₂CF₃ 216-1 216-2 Me (CH₂)₂CF₃ 217-1 217-2 Me (CH₂)₂OMe 218-1 218-2 Me (CH₂)₂NMe₂

TABLE 2 Compounds of formula (I) wherein R₁ is cyano; R₁₁ is Cl; R₄ is —N = C(R₅)ZR₆ and Z is NR₇. Cmpd No. R₂ R₅ R₆ R₇ X R₁₃ 219 SCF₃ H CH₃ CH₃ C—Cl CF₃ 220 SO₂CF₃ H CH₃ CH₃ C—Cl CF₃ 221 SCF₃ H CH₂CN H C—Cl CF₃ 222 SCF₃ H CH₃ H C—Cl CF₃ 223 SOCF₃ H CH₂Ph H C—Cl CF₃ 224 SCF₃ H CH₂Ph H C—Cl CF₃ 225 SOCF₃ H CH₃ H C—Cl CF₃ 226 SOCF₃ H CH₃ H C—Cl CF₃ 227 SOCF₃ H CH₂CF₃ H C—Cl CF₃ 228 SO₂CF₃ H 2-propynyl H C—Cl CF₃ 229 SO₂CF₃ H CH₂Ph H C—Cl CF₃ 230 SO₂CF₃ H CH₂CF₃ H C—Cl CF₃ 231 SOCF₃ H CH₃ CH₃ C—Cl CF₃ 232 SCF₃ H CH₂CF₃ H C—Cl CF₃ 233 SCF₃ H CH₂CF₃ H C—Cl CF₃ 234 SCF₃ H 2-propenyl H C—Cl CF₃ 235 SCF₃ H 2-propynyl H C—Cl CF₃ 236 SOCF₃ H 2-propynyl H C—Cl CF₃ 237 SCF₃ H CH₂OEt H N CF₃ 238 SCF₃ H CH₂OCH₂CF₃ CH₃ C—Cl CF₃ 239 SO₂CF₃ H CH₂CF₃ CH₃ C—Cl SF₅ 240 SCF₃ H CH₂CF₃ H N SF₅ 241 SOCF₃ H CH₂CH₂CF₃ H C—Cl CF₃ 242 SO₂CF₃ H (CH₂)₃CF₃ H C—Cl CF₃ 243 SCF₃ H (CH₂)₂N(CH₃)₂ H C—Cl CF₃ 244 SO₂CF₃ CH₃ CH₂(4-Cl Ph) H C—Cl CF₃ 245 SCF₃ H CH₂SO₂CF₃ H C—Cl CF₃ 246 SCF₃ H CH₂(4-pyridyl) H C—Cl CF₃ 247 SCF₃ H CH₂(3-NO₂ Ph) H C—Cl CF₃ 248 SCF₃ H CH₂CH₂SCH₃ H C—Cl CF₃ 249 SOCF₃ H CH₂CF₃ CH₃ C—Cl CF₃ Note Compounds 225 and 226 are regioisomers of the same molecular formula. In one, R₅ is H and R₆ is methyl; and in the other, R₅ is methyl and R₆ is H, but they cannot be distinguished. Also note Compound number 232 is the acetate salt, and compound number 233 is the citrate salt.

TABLE 3 Compounds of formula (I) wherein R₁ is cyano; R₁₁ is Cl; and R₄ is —N = C(R₅)—N(R₇)—R₈. Cmpd No. R₂ R₅ R₈ R₇ X R₁₃ 250 SCF₃ H OEt H C—Cl CF₃ 251 SCF₃ H NHCH₃ H C—Cl CF₃ 252 SCF₃ H NHCH₃ CH₃ C—Cl CF₃ 253 SCF₃ H OCH₂CF₃ H C—Cl CF₃ 254 SCF₃ H N(CH₃)₂ H N SF₅ 255 SCF₃ H NH₂ H C—Cl CF₃ 256 SCF₃ H S-nPr H C—Cl CF₃ 257 SO₂CF₃ Et S-nPr H C—Cl SF₅ 258 SCF₃ H SO₂CH₃ H C—Cl CF₃

The following compounds of formula (XX) are preferred according to the present invention as listed in Tables 4-12.

TABLE 4 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is SCF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₇ and R₂₀₈ = H; R₂₁₁ is Cl, X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆  1-1  1-2 Me H  2-1  2-2 Me OMe  3-1  3-2 Me OEt  4-1  4-2 Me O-i-Pr  5-1  5-2 Me O-n-Bu  6-1  6-2 Et H  7-1  7-2 Et OMe  8-1  8-2 Et OEt  9-1  9-2 Et O-i-Pr 10-1 10-2 Et O-n-Bu 11-1 11-2 n-Pr H 12-1 12-2 n-Pr OMe 13-1 13-2 n-Pr OEt 14-1 14-2 n-Pr O-i-Pr 15-1 15-2 n-Pr O-n-Bu 16-1 16-2 i-Pr H 17-1 17-2 i-Pr OMe 18-1 18-2 i-Pr OEt 19-1 19-2 i-Pr O-i-Pr 20-1 20-2 i-Pr O-n-Bu 21-1 21-2 n-Bu H 22-1 22-2 n-Bu OMe 23-1 23-2 n-Bu OEt 24-1 24-2 n-Bu O-i-Pr 25-1 25-2 n-Bu O-n-Bu 26-1 26-2 CH₂Cy H 27-1 27-2 CH₂Cy OMe 28-1 28-2 CH₂Cy OEt 29-1 29-2 CH₂Cy O-i-Pr 30-1 30-2 CH₂Cy O-n-Bu 31-1 31-2 CH₂CCH H 32-1 32-2 CH₂CCH OMe 33-1 33-2 CH₂CCH OEt 34-1 34-2 CH₂CCH O-i-Pr 35-1 35-2 CH₂CCH O-n-Bu 36-1 36-2 Me OAc 37-1 37-2 Me CH₂OMe 38-1 38-2 Me CH₂OEt 39-1 39-2 Me O-i-Pr 40-1 40-2 Me O-n-Bu 41-1 41-2 Me OCH₂CF₃

TABLE 5 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₇ and R₂₀₈ = H; R₂₁₁ is Cl, X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆  1-3  1-4 Me H  2-3  2-4 Me OMe  3-3  3-4 Me OEt  4-3  4-4 Me O-i-Pr  5-3  5-4 Me O-n-Bu  6-3  6-4 Et H  7-3  7-4 Et OMe  8-3  8-4 Et OEt  9-3  9-4 Et O-i-Pr 10-3 10-4 Et O-n-Bu 11-3 11-4 n-Pr H 12-3 12-4 n-Pr OMe 13-3 13-4 n-Pr OEt 14-3 14-4 n-Pr O-i-Pr 15-3 15-4 n-Pr O-n-Bu 16-3 16-4 i-Pr H 17-3 17-4 i-Pr OMe 18-3 18-4 i-Pr OEt 19-3 19-4 i-Pr O-i-Pr 20-3 20-4 i-Pr O-n-Bu 21-3 21-4 n-Bu H 22-3 22-4 n-Bu OMe 23-3 23-4 n-Bu OEt 24-3 24-4 n-Bu O-i-Pr 25-3 25-4 n-Bu O-n-Bu 26-3 26-4 CH₂Cy H 27-3 27-4 CH₂Cy OMe 28-3 28-4 CH₂Cy OEt 29-3 29-4 CH₂Cy O-i-Pr 30-3 30-4 CH₂Cy O-n-Bu 31-3 31-4 CH₂CCH H 32-3 32-4 CH₂CCH OMe 33-3 33-4 CH₂CCH OEt 34-3 34-4 CH₂CCH O-i-Pr 35-3 35-4 CH₂CCH O-n-Bu 36-3 36-4 Me OAc 37-3 37-4 Me CH₂OMe 38-3 38-4 Me CH₂OEt 39-3 39-4 Me O-i-Pr 40-3 40-4 Me O-n-Bu 41-3 41-4 Me OCH₂CF₃ Compound 3-3 was separated into its enantiomers (R)3-3 and (S)3-3.

TABLE 6 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)₂CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₇ and R₂₀₈ = H; R₂₁₁ is Cl, X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆  1-5  1-6 Me H  2-5  2-6 Me OMe  3-5  3-6 Me OEt  4-5  4-6 Me O-i-Pr  5-5  5-6 Me O-n-Bu  6-5  6-6 Et H  7-5  7-6 Et OMe  8-5  8-6 Et OEt  9-5  9-6 Et O-i-Pr 10-5 10-6 Et O-n-Bu 11-5 11-6 n-Pr H 12-5 12-6 n-Pr OMe 13-5 13-6 n-Pr OEt 14-5 14-6 n-Pr O-i-Pr 15-5 15-6 n-Pr O-n-Bu 16-5 16-6 i-Pr H 17-5 17-6 i-Pr OMe 18-5 18-6 i-Pr OEt 19-5 19-6 i-Pr O-i-Pr 20-5 20-6 i-Pr O-n-Bu 21-5 21-6 n-Bu H 22-5 22-6 n-Bu OMe 23-5 23-6 n-Bu OEt 24-5 24-6 n-Bu O-i-Pr 25-5 25-6 n-Bu O-n-Bu 26-5 26-6 CH₂Cy H 27-5 27-6 CH₂Cy OMe 28-5 28-6 CH₂Cy OEt 29-5 29-6 CH₂Cy O-i-Pr 30-5 30-6 CH₂Cy O-n-Bu 31-5 31-6 CH₂CCH H 32-5 32-6 CH₂CCH OMe 33-5 33-6 CH₂CCH OEt 34-5 34-6 CH₂CCH O-i-Pr 35-5 35-6 CH₂CCH O-n-Bu 36-5 36-6 Me OAc 37-5 37-6 Me CH₂OMe 38-5 38-6 Me CH₂OEt 39-5 39-6 Me O-i-Pr 40-5 40-6 Me O-n-Bu 41-5 41-6 Me OCH₂CF₃

TABLE 7 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is SCF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₁₁ is Cl; X₁ is C—Cl; and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃= SF₅) R₂₀₅ R₂₀₆ R₂₀₇, R₂₀₈ 1-7 1-8 Me H —CH₂CH₂CH₂O— 2-7 2-8 Et H —CH₂CH₂CH₂O— 3-7 3-8 i-Pr H —CH₂CH₂CH₂O— 4-7 4-8 n-Pr H —CH₂CH₂CH₂O— 5-7 5-8 n-Bu H —CH₂CH₂CH₂O— 6-7 6-8 Cy H —CH₂CH₂CH₂O— 7-7 7-8 CH₂Cy H —CH₂CH₂CH₂O— (S)1-7     — Me H —CH₂CH₂CH₂O— (R)1-7    — Me H —CH₂CH₂CH₂O— Compound 1-7 was separated into its enantiomers, called (R)1-7 and (S)1-7.

TABLE 8 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₁₁ is Cl, X₁ is C—Cl; and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆ R₂₀₇, R₂₀₈ 1-9 1-10 Me H —CH₂CH₂CH₂O— 2-9 2-10 Et H —CH₂CH₂CH₂O— 3-9 3-10 i-Pr H —CH₂CH₂CH₂O— 4-9 4-10 n-Pr H —CH₂CH₂CH₂O— 5-9 5-10 n-Bu H —CH₂CH₂CH₂O— 6-9 6-10 CH₂Cy H —CH₂CH₂CH₂O— 7-9 7-10 Cy H —CH₂CH₂CH₂O— Compound 1-9 was separated into its diastereomers, (R,R)1-9, (S,R)1-9, (S,S)1-9, (R,S)1-9. The first designation of absolute configuration refers to the configuration of the sulfoxide moiety, the second to the chiral carbon.

TABLE 9 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)₂CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₁₁ is Cl; X₁ is C—Cl; and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆ R₂₀₇, R₂₀₈ 1-11 1-12A Me H —CH₂CH₂CH₂O— 2-11 2-12A Et H —CH₂CH₂CH₂O— 3-11 3-12A i-Pr H —CH₂CH₂CH₂O— 4-11 4-12A n-Pr H —CH₂CH₂CH₂O— 5-11 5-12A n-Bu H —CH₂CH₂CH₂O— 6-11 6-12A Cy H —CH₂CH₂CH₂O— 7-11 7-12A CH₂Cy H —CH₂CH₂CH₂O— Compound 1-11 was also separated into its diastereomers, (R)1-11 and (S)1-11.

TABLE 10 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₇ and R₂₀₈ are H; R₂₁₁ is Cl, X₁ is C—Cl; and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₆ R₂₀₂ = SCF₃  1-12  1-13 Cy H  2-12  2-13 Cy OMe  3-12  3-13 Cy OEt  4-12  4-13 Cy i-O-Pr  5-12  5-13 Cy O-n-Bu R₂₀₂ = S(O)CF₃  6-12  6-13 Cy H  7-12  7-13 Cy OMe  8-12  8-13 Cy OEt  9-12  9-13 Cy O-i-Pr 10-12 10-13 Cy O-n-Bu R₂₀₂ = S(O)₂CF₃ 11-12 11-13 Cy H 12-12 12-13 Cy OMe 13-12 13-13 Cy OEt 14-12 14-13 Cy O-i-Pr 15-12 15-13 Cy O-n-Bu

TABLE 11 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₄ is —N(R₂₀₅)C(O)OR₂₀₇; R₂₁₁ is Cl; X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) R₂₀₅ R₂₀₇ R₂₀₂ is SCF₃  67-1 67-2 Me Me  68-1 68-2 Me Et  69-1 69-2 Me i-Pr  70-1 70-2 Me n-Pr  71-1 71-2 Et Me  72-1 72-2 Et Et  73-1 73-2 Et i-Pr  74-1 74-2 Et n-Pr  75-1 75-2 n-Pr Me  76-1 76-2 n-Pr Et  77-1 77-2 n-Pr i-Pr  78-1 78-2 n-Pr n-Pr  79-1 79-2 i-Pr Me  80-1 80-2 i-Pr Et  81-1 81-2 i-Pr i-Pr  82-1 82-2 i-Pr n-Pr R₂₀₂ is S(O)CF₃  83-1 83-2 Me Me  84-1 84-2 Me Et  85-1 85-2 Me i-Pr  86-1 86-2 Me n-Pr  87-1 87-2 Et Me  88-1 88-2 Et Et  89-1 89-2 Et i-Pr  90-1 90-2 Et n-Pr  91-1 91-2 n-Pr Me  92-1 92-2 n-Pr Et  93-1 93-2 n-Pr i-Pr  94-1 94-2 n-Pr n-Pr  95-1 95-2 i-Pr Me  96-1 96-2 i-Pr Et  97-1 97-2 i-Pr i-Pr  98-1 98-2 i-Pr n-Pr R₂₀₂ is S(O)₂CF₃  99-1 99-2 Me Me 100-1 100-2  Me Et 101-1 101-2  Me i-Pr 102-1 102-2  Me n-Pr 103-1 103-2  Et Me 104-1 104-2  Et Et 105-1 105-2  Et i-Pr 106-1 106-2  Et n-Pr 107-1 107-2  n-Pr Me 108-1 108-2  n-Pr Et 109-1 109-2  n-Pr i-Pr 110-1 110-2  n-Pr n-Pr 111-1 111-2  i-Pr Me 112-1 112-2  i-Pr Et 113-1 113-2  i-Pr i-Pr 114-1 114-2  i-Pr n-Pr

TABLE 12 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇ R₂₀₈; R₂₁₁ is Cl; X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Com- Com- pound pound Number Number (R₂₁₃ = (R₂₁₃ = CF₃) SF₅) h R₂₀₅ R₂₀₆ R₂₀₇ R₂₀₈ 115-1 115-2 0 Me H Me Me 116-1 116-2 0 Me OEt H Me 117-1 117-2 0 Me H —CH₂CH₂— 118-1 118-2 0 Me OMe H Me 119-1 119-2 0 Me OEt Me Me 120-1 120-2 2 Me OCH₂CH₂OMe H H 121-1 121-2 0 Me H —CH₂CH₂CH₂CH₂O— 122-1 122-2 1 Me OEt H Me 123-1 123-2 0 Me H H Me 124-1 124-2 0 Me H H Et

TABLE 13 Compounds of formula (XX) wherein R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is N(R₂₀₅)C(O)aryl; R₂₀₅ is CH₃; R₂₁₁ is Cl; X₁ is C—Cl, and R₂₁₃ is CF₃ or SF₅. Within this table the following symbols are defined: Ph means phenyl; Fu means furyl; Th means the thiophene radical, i.e., thienyl; Pyr means pyridyl. Compound Compound Number Number (R₂₁₃ = CF₃) (R₂₁₃ = SF₅) Aryl R₂₀₂ is SCF₃ 125-1 125-2 Ph 126-1 126-2 4-OMe-Ph 127-1 127-2 4-CF₃-Ph 128-1 128-2 2-Th 129-1 129-2 3-Th 130-1 130-2 2-Fu 131-1 131-2 3-Fu 132-1 132-2 2-Pyr 133-1 133-2 3-Pyr 134-1 134-2 4-Pyr 135-1 135-2 6-Cl-2-Pyr 136-1 136-2 6-CF₃-2-Pyr 137-1 137-2 5-Cl-2-Fu 138-1 138-2 5-CF₃-2-Fu 139-1 139-2 5-OMe-2-Th 140-1 140-2 5-CF₃-2-Th R₂₀₂ is S(O)CF₃ 125-3 125-4 Ph 126-3 126-4 4-OMe-Ph 127-3 127-4 4-CF₃-Ph 128-3 128-4 2-Th 129-3 129-4 3-Th 130-3 130-4 2-Fu 131-3 131-4 3-Fu 132-3 132-4 2-Pyr 133-3 133-4 3-Pyr 134-3 134-4 4-Pyr 135-3 135-4 6-Cl-2-Pyr 136-3 136-4 6-CF₃-2-Pyr 137-3 137-4 5-Cl-2-Fu 138-3 138-4 5-CF₃-2-Fu 139-3 139-4 5-OMe-2-Th 140-3 140-4 5-CF₃-2-Th R₂₀₂ is S(O)₂CF₃ 125-5 125-6 Ph 126-5 126-6 4-OMe-Ph 127-5 127-6 4-CF₃-Ph 128-5 128-6 2-Th 129-5 129-6 3-Th 130-5 130-6 2-Fu 131-5 131-6 3-Fu 132-5 132-6 2-Pyr 133-5 133-6 3-Pyr 134-5 134-6 4-Pyr 135-5 135-6 6-Cl-2-Pyr 136-5 136-6 6-CF₃-2-Pyr 137-5 137-6 5-Cl-2-Fu 138-5 138-6 5-CF₃-2-Fu 139-5 139-6 5-OMe-2-Th 140-5 140-6 5-CF₃-2-Th

The present invention also relates to a composition comprising a parasiticidally effective, substantially non-emetic amount of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof and an acceptable carrier. Acceptable carriers for the use of the compounds are generally known to the skilled addressee concerned with arthropod pest control in animals, particularly domestic animals, most preferably dogs or cats.

The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof. The remainder of the composition up to 100% comprises a carrier as well as generally various additives. In this specification and the accompanying claims, percentages are by weight.

The diluted liquid formulations generally comprise from about 0.001 to about 3% of compound of formula (I) or a salt thereof or compound of formula (XX) or a salt thereof, preferably from about 0.1 to about 0.5%.

Solid formulations generally comprise from about 0.1 to about 8% of compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, preferably from about 0.5 to about 1.5%.

Compositions for oral administration comprise one or more of the compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof in association with veterinarily acceptable carriers or coatings and include, for example, tablets, pills, capsules, gels, drenches, medicated feeds, medicated drinking water, medicated dietary supplements, slow-release boluses or other slow-release devices intended to be retained within the gastrointestinal tract. Any of these may incorporate the active ingredients contained within micro-capsules or coated with acid-labile or alkali-labile or other pharmaceutically acceptable enteric coatings. Feed premixes or concentrates containing compounds of the present invention for use in preparation of medicated diets, drinking water or other materials for consumption by animals may also be used. In a highly preferred embodiment, the compositions are administered postprandially, preferably from just after a meal to 2 hours after the meal.

In a highly preferred embodiment, there is provided a product which is readily chewed by the animal and which product does generally not allow human contamination when the product is provided to the animal by hand.

The compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof may be administered before, during or after meals. The compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof may be mixed with a carrier and/or a foodstuff.

According to the present invention the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof formula (I) is administered orally in a dose to the animal in a dose range generally from 0.1 to 500 mg/kg of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof (I) per kilogram of animal body weight (mg/kg), preferably from 1 to 100 mg/kg, more preferably from 1 to 50 mg/kg, even more preferably from 2 to 25 mg/kg, most preferably from 3 to 15 mg/kg.

According to the present invention, the frequency of treatment of the animal, preferably the domestic animal to be treated by the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, is generally from about once per week to about once per year, preferably from about once every two weeks to about once every six months, more preferably from about once every two weeks to once every three months, even more preferably from about once every two weeks to about once every six weeks, and most preferably from about once every three weeks to about once every five weeks. Most highly desirable treatment is about once a month.

Generally the animal to be treated is a domestic animal, preferably a domestic companion animal. More preferably the animal to be treated is a dog and/or a cat.

The compounds of the invention may be administered most advantageously with another parasiticidally effective material, such as an endoparasiticide, and/or an ectoparasiticide, and/or an endectoparasiticide. For example, such compounds include, namely macrocyclic lactones such as avermectins or milbemycins e.g., ivermectin; pyratel (generally administered as pyrantel pamoate) or an insect growth regulator such as lufenuron or methoprene.

By the term “parasites” as used in the specification and claims is meant endoparasites and ectoparasites of warm-blooded animals, particularly ectoparasites. Preferably, fleas and/or ticks are controlled by the method of the present invention.

Illustrative of specific parasites of various host animals which may be controlled by the method of this invention include arthropods such as:

Mites: Mesostigmata spp. e.g. mesostigmatids such as the chicken mite, Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp. for example Sarcoptes scabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g. Trombiculidae spp. for example the north american chigger, Trombicula alfreddugesi;

Ticks: e.g., soft-bodied ticks including Argasidae spp. for example Argas spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example Rhipicephalus sanguineus, and Boophilus spp.;

Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;

Fleas: e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans);

True bugs: e.g., Cimicidae or including the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius proilxus and Triatoma spp.;

bloodsucking adult flies: (e.g., horn fly [Haematobia irritans], horse fly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly [Simulium spp.], deer fly [Chrysops spp.], louse fly [Melophagus ovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anopheles spp., and Aedes spp.]); and

parasitic fly maggots: (e.g., bot fly [Oestrus ovis and Cuterebra spp.], blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax], cattle grub [Hypoderma spp.], fleeceworm).

The present invention also relates to a use of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof hereinbefore described as a therapeutic agent, preferably for animals, more preferably for domestic animals.

The veterinary composition may be sterile or non-sterile. It may be a liquid (e.g., aqueous) or solid (e.g., dry) composition, in particular a freeze-dried composition, from which, by addition of water or another liquid, orally effective solutions may be prepared.

The present invention also relates to a use of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined for the manufacture of a veterinary composition for the control of parasites in or on an animal.

The present invention also relates to a method of cleaning animals in good health comprising the application to the animal of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined to the animal.

The method of cleaning an animal is not a method of treatment by therapy of the animal body per se, because

(a) the animal is in good health and requires no substantial treatment to correct a deficiency of health;

(b) the cleaning of the animal is not intended to be done by veterinary personnel, but by persons interested in the cleaning of the animal; and

(c) the purpose of such cleaning is to avoid unpleasant conditions for humans and the environment which humans inhabit so as to not infest the said humans with arthropods carried by the animal.

By “carrier” is meant an organic or inorganic material, which can be natural or synthetic, and which is associated with the compound and which facilitates its application to the animal. This carrier is thus generally inert and should be arthropocidally acceptable. The carrier can be solid (e.g., clay, silicates, silica, resins, wax) or liquid (e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents). An example of an oil solvent is corn oil. An example of a polar aprotic solvent is dimethyl sulfoxide.

The compounds of formula (II) wherein R₂₁, R₂₂, R₂₄, R₃₁, R₃₃ and X are as defined above may be prepared from the compounds of formula (III):

wherein R₂₁, R₂₂, R₃₁, R₃₃ and X are as defined above, using processes described in European Patent Publications 0511845 or 0659745, incorporated by reference herein and relied upon.

According to a feature of the present invention, compounds of formula (II) wherein R₂₁, R₂₂, R₃₁, R₃₃ and X are as defined above and R₂₄ is —N═C(R₂₅)—NR₂₆R₂₇ wherein R₂₅, R₂₆ and R₂₇ are as defined above may be prepared by reacting a compound of formula (III) with a compound of formula (IV):

wherein R₂₅, R₂₆ and R₂₇ are as defined above and R₁₀₀ is generally an alkyl group. The reaction is optionally conducted in the presence of a catalyst such as a mineral or organic acid (for example hydrochloric acid), generally using from 1 to 100 equivalents of (IV), preferably using 1 to 10 equivalents of (IV), and is preferably conducted in an organic solvent such as tetrahydrofuran, toluene, or N,N-dimethylformamide, at a temperature of from 0° C. to 150° C. Additional adjuvants such as drying agents (e.g., magnesium sulfate, potassium carbonate, or molecular sieves) may also be advantageous to the reaction. Compounds of formula (IV) are known or may be prepared by known procedures.

According to a feature of the present invention, compounds of formula (II) wherein R₂₁, R₂₂, R₃₁, R₃₃ and X; are as defined above and R₂₄ is —N═C(R₂₅)—NR₂₆R₂₇ wherein R₂₅, R₂₆ and R₂₇ are as defined above, may be prepared by the reaction of a compound of formula (V):

wherein R₂₁, R₂₂, R₂₅, R₃₁, R₃₃, X and R₁₀₀ are as defined above, with a compound of formula (VI):

wherein R₂₆ and R₂₇ are as defined above. The reaction is generally conducted using the same conditions as used for the preparation of compounds of formula (II) by the reaction of compounds of formula (III) with compounds of formula (IV).

According to a feature of the present invention, compounds of formula (II) wherein R₂₄ is —N═C(R₂₅)—NR₂₇R₂₈, and R₂₁, R₂₂, R₂₅, R₂₇, R₃₁, R₃₃ and X are as defined above, and R₂₈ is COR₃₄ wherein R₃₄ is as defined above, may be prepared by the reaction of the corresponding compounds of formula (II) wherein R₂₄ is —N═C(R₂₅)—NR₂₇H with an acid chloride of formula (VII):

R₃₄COCl  (VII)

wherein R₃₄ is as defined above. The reaction is generally performed in the presence of a base such as a trialkylamine, for example triethylamine, in a solvent such as dichloromethane, at a temperature of from 0° C. to 50° C.

According to a feature of the present invention, compounds of formula (II) wherein R₂₄ is —N═C(R₂₅)—NR₂₇R₂₈, and R₂₁, R₂₂, R₂₅, R₂₇, R₃₁, R₃₃ and X are as defined above and R₂₈ is —S(O)_(t)R₃₀ may be prepared by the reaction of the corresponding compound of formula (II) wherein R₂₄ is —N═C(R₂₅)—NR₂₇H with a sulfonyl chloride or a sulfenyl chloride of formula (VIII):

R₃₀S(O)_(t)Cl  (VIII)

The reaction is generally performed in the presence of a weak base such as a trialkylamine for example triethylamine, or pyridine in a solvent such as dichloromethane, at a temperature of from 0° C. to 50° C.

Compounds of formulae (VI), (VII) and (VIII) are known or may be prepared by known procedures.

Compounds of formulae (III) and (V) may be generally prepared according to known processes, for example as described in International Patent Publications WO 87/03781, WO 93/06089, and WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0846686, and U.S. Pat. No. 5,232,940.

In another aspect of the present invention, compounds of formula (XX) wherein R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈, N(R₂₀₅)C(O)aryl, or N(R₂₀₅)C(O)OR₂₀₇ are generally prepared from compounds of formula (XXI):

by reaction with halides of formulae X₂C(O)CR₂₀₆R₂₀₇R₂₀₈, X₂C(O)aryl or X₂C(O)OR₂₀₇, respectively, wherein R₂₀₁, R₂₀₂, R₂₀₅, R₂₀₆, R₂₀₇, R₂₀₈, R₂₁₁, R₂₁₃, and X₁ are defined above and wherein X₂ is a halogen atom. The reaction is generally carried out in the presence of a base, generally using from 1 to 10 molar equivalents of the halide, and is preferably conducted in the presence of an organic solvent such as tetrahydrofuran, methylene chloride, at a temperature of from 0° C. to 150° C.

Compounds of formula (XXI) may be prepared from a compound of formula (XXII):

by reaction with a compound of formula (XXIII):

X₂R₂₀₅  (XXIII)

wherein R₂₀₁, R₂₀₂, R₂₀₅, R₂₁₁, R₂₁₃, X₁ and X₂ are defined above. Compounds of formula (XXIII) are generally known in the art as alkylhalides or substituted alkylhalides. Compounds of formula (XXII) may be prepared by methods described in International Patent Publications WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0659745, 0846686, and U.S. Pat. No. 5,232,940, or other methods known to the person skilled in the art.

Alternatively compounds of formula (XXI) may be prepared by reduction of compounds of formula (XXIV):

wherein R₂₀₁, R₂₀₂, R₂₁₁, R₂₁₃ and X₁ are defined above. The reduction generally is effected by the use of a standard hydride ion donor, for example sodium borohydride or sodium cyanoborohydride. The reaction is generally effected in an polar solvent such as ethanol or methanol and generally using from 1 to 10 molar equivalents of the hydride, and is preferably conducted at a temperature of from −100° C. to 150° C.

Compounds of formula (XXIV) may be prepared using methods described in EP 0295117, WO 97/22593 or other methods known to those skilled in the art.

In another aspect of the invention there are provided the compounds 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole and 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole which are useful intermediates for the preparation of compounds for use according to the present invention.

BIOLOGICAL EXAMPLE 1

Compounds 1-1, 2-1, 3-1, 4-1, 11-1, 13-1, 28-1, 31-1, 32-1, 36-1, 37-1, 38-1, 1-3, 2-3, 3-3, 4-3, 6-3, 41-3, 1-5, 2-5, 3-5, 6-5, 11-5, 27-5, 28-5, 1-7, 3-7, 5-7, 1-9, 1-11, 6-11, 7-11, 1-12, 11-12, ₁3-12, 67-1, 68-1, 69-1, 70-1, 72-1, 75-1, 76-1, 77-1, 78-1, 79-1, 80-1, 81-1, 82-1, 115-1, 116-1, 117-1, 118-1, 119-1, 120-1, 121-1, 122-1, 123-1, 124-1, 211-1, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, (R)3-3, (S)3-3, (R)1-7, (S)1-7, (R,S)1-9, (R,R)1-9, (S,R)1-9, (S,S) 1-9, (S)1-11, (R)1-11, 126-1, 127-1 and 130-1 were each formulated as a 30 mg/mL formulation in a 1:1 volume/volume solution of dimethyl sulfoxide and corn oil. Using this formulation, mixed breed dogs and cats were treated at a rate of 10 mg of the compound per kg (mg/kg)of body weight of the dog and 20 mg/kg of the cat treated. The animals were fasted for at least 8 hours prior to treatment, fed half of the daily ration immediately prior to treatment, then allowed access to the remainder of the daily ration immediately following treatment.

All dogs were infested with cat fleas (Ctenocephalides felis) and with ticks (Rhipicephalus sanguineus) 1 day prior to administration of the compound. Cats were only infested with fleas. The initial flea and tick counts were performed 1 day after the administration of the compounds. At 7, 14, 21 and 28 days after treatment the dogs were re-infested with ticks and 8, 15, 22 and 29 days after treatment the dogs and cats were re-infested with fleas. At 1, 9, 16, 23 and 30 days after treatment the control of fleas and ticks in treated dogs and cats was determined versus a group of infested dogs and cats which received a placebo consisting of a 1:1 volume/volume solution of dimethyl sulfoxide and corn oil. To determine the efficacies of the compounds, the arthropods were combed from the animals and counted.

In the animals treated with the compounds above, there was substantially no emesis after 2, 8 and 24 hours. Generally long-term control of fleas and ticks was provided in dogs. In the cats treated, there was commercially acceptable control of fleas for at least one day post treatment.

The results of this example were superior to those obtained with compounds of the prior art, for example, fipronil.

BIOLOGICAL EXAMPLE 2

The compounds listed below were formulated and tested as described in Biological Example 1, again at the dosage level of active ingredient of 10 mg/kg in dogs and 20 mg/kg in cats. Results at 1 DPT (day post-treatment) are tabulated below, where the compound numbers are the same as those listed in Tables 1, 2, 4, 5, 6, 7, 8, 9 10, 11, 12 and 13 hereinabove.

DOG TESTING RESULTS % Control 1 DPT Compound Number (Fleas/Ticks) % Emesis 211-1  99/51 0 219 97/80 33  224 38/6  0 230 100/80  0 232 99/35 0 233 100/77  0 1-1 91/82 0 2-1 100/100 0 3-1 100/96  0 13-1  99/97 0 28-1  89/75 0 36-1  71/92 0 1-3 94/95 0 2-3 100/99  33  3-3 100/98  0 4-3 100/100 33  41-3  100/98  33  1-5 98/84 0 2-5 100/95  33  3-5 100/100 33  27-5  100/100 0 28-5  100/74  0 1-7 100/97  0 3-7 100/100 0 7-7 29/66 0 1-9 100/100 0  1-11 100/100 0  6-11 100/98  0  7-11 100/100 0  3-12 99/97 0 67-1  100/100 33  68-1  100/77  0 69-1  98/94 0 70-1   99/100 0 71-1  100/100 0 72-1  100/97  0 73-1  100/100 0 74-1  99/87 0 75-1  89/57 0 76-1  100/86  0 77-1  98/10 0 78-1  96/94 0 79-1  96/86 0 80-1  100/94  0 81-1  76/66 0 82-1  86/90 0 116-1   79/100 0 120-1  97/78 0 122-1  100/95  0 123-1  74/0  0 126-1  31/45 0 127-1  100/97  0 130-1  100/100 0

CAT TESTING RESULTS % Control 1 DPT Compound Number (Fleas) % Emesis 219 100 25  230  98 0 232 100 0 233  95 0 1-1  99 0 2-1 100 0 3-1 100 0 13-1   61 0 28-1  100 0 36-1  100 25  37-1   76 0 38-1   87 0 1-3  87 0 2-3 100 0 3-3 100 0 4-3 100 25  1-5  0 33  2-5 100 0 3-5 100 0 27-5  100 0 1-7 100 25  3-7 100 0 8-7 100 0 (S)1-7    99 0 (R)1-7    100 0 1-9 100 0  1-11  98 0  6-11  98 0  7-11 100 0  1-12  79 0  3-12  97 25  67-1   53 0 68-1  100 0 69-1  100 0 70-1   85 0 71-1  100 50  72-1   99 0 73-1   93 0 74-1  100 0 75-1   71 25  76-1  100 0 77-1   99 0 79-1   87 0 80-1   99 0 81-1  100 0 82-1   93 0 116-1  100 0 117-1   45 0 119-1   99 0 120-1  100 0 121-1  100 0 123-1  100 25  124-1   92 0 126-1   99 0 127-1   84 0 130-1   93 25 

BIOLOGICAL EXAMPLE 3

A representative compound of formula (XX) of the invention was compared with a representative compound of Huang et al U.S. Pat. No. 5,556,873. The compounds tested were the following:

Compound of the Invention: 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-(N-methyl)methoxyacetamidopyrazole

Huang et al Compound #1: 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-(methoxyacetamido)pyrazole

Testing was carried out as described in Biological Example 1. The compound of the invention, tested in a group of 3 dogs at 10 mg/kg, gave 93% control of fleas even at 30 DPT and 100% control of ticks at 30 DPT, with no emesis (0/3); tested in a group of 4 cats at 20 mg/kg, the compound of the invention gave 100% control of fleas for at least a one month period with no vomiting. In contrast, the Huang et al compound, tested in a group of 3 dogs at 10 mg/kg, gave <50% control of fleas after only 9 DPT and <50% control of ticks after 9 DPT, with no emesis (0/3). The Huang et al compound was deemed to have insufficient activity to be tested in cats.

The following non-limiting Synthesis Examples illustrate the preparation of compounds of formula (I) and the Reference Examples illustrate the preparation of intermediates used in their synthesis.

SYNTHESIS EXAMPLE 1

A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole (1 g) in N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 1 hour. Evaporation of solvents gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N′-dimethylaminomethylideneamino-4-trifluoromethylthiopyrazole m.p. 141° C.

By proceeding in a similar manner the following compounds were also prepared:

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N′-dimethylaminomethylideneamino-4-trifluoromethylsulfonylpyrazole m.p. 209° C.; and

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-N′-dimethylaminomethylideneamino-4-trifluoromethylsulfinylpyrazole m.p. 207° C.

SYNTHESIS EXAMPLE 2

A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (5 g) in ethanol was treated with benzylamine (11.4 ml), stirred overnight, evaporated and purified by reverse-phase column chromatography (C-18 stationary phase column, eluting with MeOH/water) to give 5-N′-benzylaminomethylideneamino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (1.18 g), m.p. 113° C.

By proceeding in a similar manner the compounds of formula (II) wherein R₂₁ is CN; R₂₄ is —N═CH—NHR₂₆; R₃₁ is Cl; X is C—Cl; and R₃₃ is CF₃ shown in the Table below were also prepared.

TABLE Compound No. R₂₂ R₂₆ M.P. ° C.  21 SCF₃ CH₂CN 175 211-1 SCF₃ CH₂CF₃ 130 222 SCF₃ CH₃ 173 223 SOCF₃ CH₂Ph 173 225 SOCF₃ CH₃ 144 226 SOCF₃ CH₃ 144 227 SOCF₃ CH₂CF₃ 175 228 SO₂CF₃ 2-propynyl 149 229 SO₂CF₃ CH₂Ph 182 230 SO₂CF₃ CH₂CF₃ 183 209-1 SCF₃ iPr 207-1 SCF₃ CH₂CH₃ 141

REFERENCE EXAMPLE 1

A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (500 g) in triethyl orthoformate was treated with concentrated hydrochloric acid (10 ml) and heated at 50° C. After 8 hours the reaction mixture was evaporated to give a solid which was washed (heptane) and air-dried to give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (217 g), m.p. 68° C.

By proceeding in a similar manner the following intermediates were also prepared:

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole, m.p.63° C.; and

3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfonylpyrazole, m.p. 118° C.

SYNTHESIS EXAMPLE 3

3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (111.55 g, 0.247 mole), triethylamine (62.45 g, 0.618 mole), 4-dimethylaminopyridine (3 g, 0.0247 mole), and tetrahydrofuran (700 ml) was combined. The resulting solution was heated to 45° C. and ethoxyacetyl chloride (45.2 g, 0.37 mmol) was added dropwise over 10 min. After 1 h, the mixture was evaporated to a brown residue, which was dissolved in 500 ml of ethyl acetate and washed with 2×300 ml of water. The organic phase was dried over magnesium sulfate, filtered, and evaporated to a brown oil. The oil was triturated with 1 L of hot cyclohexane. The resulting solids were collected by filtration and washed with 500 ml of hot cyclohexane, then air dried to afford compound 3-3 as a beige powder (116.7 g). Evaporation of the mother liquors afforded a second crop of compound 3-3 (8.4 g).

In a similar fashion or by modifications according to methods known to the skilled addressee, the following compounds were prepared. The compound numbers in the left column refer to the Tables cited above.

Compound Mass Spectral molecular Number ion + 1 (M + 1) 1-1 477 2-1 507 3-1 521 4-1 535 11-1  505 13-1  549 28-1  537 31-1  517 32-1  531 36-1  535 37-1  521 38-1  535 1-3 593 2-3 523 3-3 537 4-3 551 6-3 491 41-3  473 1-5 509 2-5 539 3-5 553 6-5 523 11-5  537 27-5  579 28-5  593 1-7 533 3-7 561 5-7 575 1-9 549  1-11 565  6-11 591  7-11 605  1-12 535 11-12 565 13-12 579 67-1  493 68-1  507 69-1  521 70-1  521 72-1  521 75-1  521 76-1  535 77-1  549 78-1  549 79-1  521 80-1  535 81-1  549 82-1  549 115-1  505 116-1  535 117-1  503 118-1  521 119-1  549 120-1  583 121-1  547 122-1  551 123-1  491 124-1  505 126-1  507 127-1  607 130-1  529

REFERENCE EXAMPLE 2 Step A: Preparation of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole

A 12-L three-necked flask fitted with an overhead stirrer, heating mantle, water separator (e.g. Dean Stark trap) with condenser was placed under a nitrogen atmosphere and charged with 1.475 kg (3.37 moles) of fipronil and 6 L of triethyl orthoformate. The suspension was heated to reflux over 2.5 h, then at reflux for 3 h with collection and removal of the distillate. The mixture was cooled to room temperature, then evaporated under reduced pressure at a bath temperature of 60-80° C., then at 50° C. overnight. The resulting beige solid, 1.717 kg (95.8% by HPLC, 3.335 moles, 99% purity corrected yield) was used without further purification (m.p. about 63° C.).

Step B: Preparation of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole

A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfnylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 mole) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (350 g) as an off-white solid (m.p. about 227° C.).

While the invention has been described in terms of various preferred embodiments, the person skilled in the art will appreciate that various modifications, substitutions, omissions and changes can be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof. 

What is claimed is:
 1. A compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)R₂₀₃; R₂₀₃ is alkyl or haloalkyl; R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl or halocycloalkylalkyl; R₂₀₆ is alkoxy, haloalkoxy, alkoxyalkyl or haloalkoxyalkyl; R₂₀₇ and R₂₀₈ are each hydrogen; X₁ is nitrogen or C—R₂₁₂; R₂₁₁ and R₂₁₂ are, independently, halogen, hydrogen, CN or NO₂; R₂₁₃ is halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃, or —SF₅; and h and k are, independently, 0, 1 or 2; or a veterinarily acceptable salt thereof.
 2. A compound according to claim 1, wherein, in the compound of formula (XX): R₂₀₅ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or halocycloalkylalkyl; and R₂₀₆ is alkoxy or haloalkoxy.
 3. A compound according to claim 2, wherein R₂₀₂ is SCF₃.
 4. A compound according to claim 3, wherein R₂₀₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl or cyclopropylmethyl, and R₂₀₆ is methoxy, ethoxy, isopropoxy, n-butyloxy, methoxymethyl, ethoxyethyl or OCH₂CF₃.
 5. A compound according to claim 4, wherein R₂₁₃ is CF₃.
 6. The compound according to claim 5, wherein: (a) R₂₀₅ is methyl and R₂₀₆ is methoxy; (b) R₂₀₅ is methyl and R₂₀₆ is ethoxy; (c) R₂₀₅ is methyl and R₂₀₆ is isopropoxy; (d) R₂₀₅ is n-propyl and R₂₀₆ is ethoxy; (e) R₂₀₅ is cyclopropylmethyl and R₂₀₆ is ethoxy; (f) R₂₀₅ is methyl and R₂₀₆ is methoxymethyl; or (g) R₂₀₅ is methyl and R₂₀₆ is ethoxymethyl.
 7. A compound according to claim 6, wherein R₂₀₂ is S(O)CF₃.
 8. A compound according to claim 7, wherein R₂₀₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl or cyclopropylmethyl, and R₂₀₆ is methoxy, ethoxy, isopropoxy, n-butyloxy, methoxymethyl, ethoxymethyl or OCH₂CF₃.
 9. A compound according to claim 8, wherein R₂₁₃ is CF₃.
 10. The compound according to claim 9, wherein: (a) R₂₀₅ is methyl and R₂₀₆ is methoxy; (b) R₂₀₅ is methyl and R₂₀₆ is ethoxy; (c) R₂₀₅ is methyl and R₂₀₆ is isopropoxy; or (d) R₂₀₅ is methyl and R₂₀₆ is OCH₂CF₃.
 11. The compound according to claim 9, wherein R₂₀₅ is methyl and R₂₀₆ is ethoxy, said compound being the R enantiomer.
 12. The compound according to claim 9, wherein R₂₀₅ is methyl and R₂₀₆ is ethoxy, said compound being the S enantiomer.
 13. A compound according to claim 10, wherein R₂₀₂ is S(O)₂CF₃.
 14. A compound according to claim 13, wherein R₂₀₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl or cyclopropylmethyl; and R₂₀₆ is methoxy, ethoxy, isopropoxy, n-butyloxy, methoxymethyl, ethoxymethyl or OCH₂CF₃.
 15. A compound according to claim 14, wherein R₂₁₃ is CF₃.
 16. The compound according to claim 15, wherein: (a) R₂₀₅ is methyl and R₂₀₆ is methoxy; (b) R205 is methyl and R₂₀₆ is ethoxy; (c) R₂₀₅ is cyclopropylmethyl and R₂₀₆ is methoxy; or (d) R₂₀₅ is cyclopropylmethyl and R₂₀₆ is ethoxy.
 17. A compound according to claim 1, wherein R₂₀₂ is SCF₃, S(O)CF₃ or S(O)₂CF₃; R₂₁₁ is Cl; X₁ is C—Cl; R₂₁₃ is CF₃ or SF₅; R₂₀₅ is cyclopropyl; R₂₀₇ is hydrogen; R₂₀₈ is hydrogen; and R₂₀₆ is alkoxy.
 18. A compound according to claim 17, wherein R₂₀₆ is methoxy, ethoxy, isopropoxy or n-butyloxy.
 19. A compound according to claim 18, wherein R₂₁₃ is CF₃.
 20. The compound according to claim 19, wherein: (a) R₂₀₂ is S(O)₂CF₃ and R₂₀₆ is ethoxy; or (b) R₂₀₂ is SCF₃ and R₂₀₆ is ethoxy.
 21. A compound according to claim 19, wherein R₂₀₅ is alkyl; and R₂₀₆ is alkoxy.
 22. A compound according to claim 21, wherein R₂₀₅ is methyl; and R₂₀₆ is methoxy or ethoxy.
 23. A compound according to claim 22, wherein R₂₁₃ is CF₃.
 24. A compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl; R₂₀₆ is alkoxy; R₂₀₇ is hydrogen; R₂₀₈ is hydrogen; X₁ is C—Cl; R₂₁₁ is Cl; R₂₁₃ is —CF₃, or —SF₅; and h is 0, 1 or 2; or a veterinarily acceptable salt thereof.
 25. A compound according to claim 24, wherein R₂₀₅ is methyl or ethyl.
 26. A compound according to claim 24, wherein R₂₀₆ is methoxy, ethoxy, propoxy or isopropoxy.
 27. A compound according to claim 25, wherein R₂₀₆ is methoxy, ethoxy, propoxy or isopropoxy.
 28. A compound according to claim 26, wherein R₂₀₆ is methoxy or ethoxy.
 29. A compound according to claim 27, wherein R₂₀₆ is methoxy or ethoxy.
 30. A compound according to claim 28, wherein R₂₀₅ is methyl.
 31. A compound according to claim 29, wherein R₂₀₅ is methyl.
 32. A composition comprising a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)R₂₀₃; R₂₀₃ is alkyl or haloalkyl; R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl or halocycloalkylalkyl; R₂₀₆ is alkoxy, haloalkoxy, alkoxyalkyl or haloalkoxyalkyl; R₂₀₇ and R₂₀₈ are each hydrogen; X₁ is nitrogen or C—R₂₁₂; R₂₁₁ and R₂₁₂ are, independently, halogen, hydrogen, CN or NO₂; R₂₁₃ is halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃, or —SF₅; and h and k are, independently, 0, 1, or 2; or a veterinarily acceptable salt thereof; and a veterinarily acceptable carrier therefor.
 33. A veterinary composition according to claim 32 comprising, in oral unit dosage form: (a) a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX) as defined in claim 32, or a veterinarily acceptable salt thereof; and (b) a veterinarily acceptable carrier therefor.
 34. A veterinary composition according to claim 33, wherein the oral unit dosage amount of the compound of formula (XX) is from 0.1 to 500 mg per kg of animal body weight.
 35. A composition comprising a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl; R₂₀₆ is alkoxy; R₂₀₇ is hydrogen; R₂₀₈ is hydrogen; X₁ is C—Cl; R₂₁₁ is Cl; R₂₁₃ is —CF₃, or —SF₅; and h is 0, 1 or 2; or a veterinarily acceptable salt thereof; and a veterinarily acceptable carrier therefor.
 36. A veterinary composition according to claim 35 comprising, in oral unit dosage form: (a) a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX) as defined in claim 35, or a veterinarily acceptable salt thereof; and (b) a veternarily acceptable carrier therefor.
 37. A veterinary composition according to claim 36, wherein the oral unit dosage amount of the compound of formula (XX) is from 0.1 to 500 mg per kg of animal body weight.
 38. A compound according to claim 24, wherein R₂₀₂ is —SOCF₃, R₂₀₅ is methyl, R₂₀₆ is ethoxy and R₂₁₃ is CF₃.
 39. A compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl or cycloalkylalkyl; R₂₀₆ is alkoxy, alkoxyalkyl or haloalkoxy; R₂₀₇ is hydrogen; R₂₀₈ is hydrogen; R₂₁₁ is Cl; X₁ is C—Cl; R₂₁₃ is CF₃ or SF₅; and h is 0, 1 or 2; or a veterinarily acceptable salt thereof.
 40. A composition comprising a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX):

wherein: R₂₀₁ is cyano; R₂₀₂ is S(O)_(h)CF₃; R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈; R₂₀₅ is alkyl or cycloalkylalkyl; R₂₀₆ is alkoxy, alkoxyalkyl or haloalkoxy; R₂₀₇ is hydrogen; R₂₀₈ is hydrogen; R₂₁₁ is Cl; X₁ is Cl; R₂₁₃ is CF₃ or SF₅; and h is 0, 1 or 2; or a veterinarily acceptable salt thereof; and a veterinarily acceptable carrier therefor.
 41. A veterinary composition according to claim 40 comprising, in oral unit dosage form: (a) a parasiticidally effective, substantially non-emetic amount of a compound having the formula (XX) as defined in claim 40, or a veterinarily acceptable salt thereof; and (b) a veterinarily acceptable carrier therefor.
 42. A veterinary composition according to claim 41, wherein the oral unit dosage amount of the compound of formula (XX) is from 0.1 to 500 mg per kg of animal body weight. 